In order to understand the biochemical mechanisms involved in the morphine-tolerant dependent state, the role of the putative neurotransmitters in the brain will be studied. Their effects on the developmental process and the final tolerant-dependent state will be assessed. The approach will be to alter the functional state of acetylcholine, dopamine, norepinephrine, serotonin, cyclic AMP, and GABA through pharmacologic manipulation. Agents which alter the synthesis, storage, uptake, release, and degradation of the neurohormones will be studied. When possible only one brain substance will be manipulated at a time, but in order to study the importance of the balance between endogenous agents at times it may be necessary to modify the state of two or more neurohormones simultaneously. Attempts will be made to elucidate the putative transmitters involved in mediating morphine effects and in the withdrawal syndrome.